According to DSM-IV-TR, a mixed episode can occur only in bipolar I disorder (BD-I). A mixed episode requires a concurrent full-criteria major depressive episode (MDE) and a manic episode. Mixed mania has also been defined in the research as a manic episode plus three or more depressive symptoms (McElroy et al., 1992).
Until recently, mixed depression (i.e., MDE plus manic-hypomanic symptoms during the episode) was understudied. Most of the research comes from Perugi et al. (2001, 1997) in BD-I and Akiskal and Benazzi in bipolar II disorder (BD-II) and major depressive disorder (MDD) (Akiskal and Benazzi, 2003; Benazzi, 2000; Benazzi and Akiskal, 2001). Many of the main findings were replicated by Sato et al. (2003), Maj et al. (2003) and Judd et al. (2003).
This review will focus on BD-II and MDD outpatient mixed depression. The study setting is a large outpatient solo private practice in Italy that is more representative of mood disorders (apart from BD-I) usually seen in clinical practice in Italy. The most severe and socially disadvantaged (less representative) cases are usually seen through the national health service or university centers.
Community and clinical outpatient depression studies found that the BD-II to MDD ratio is near 1 (Angst et al., 2003; Benazzi, 2003a, 1997). Two long-term follow-up studies of MDD have also shown that around 50% of patients with MDD develop BD-I or BD-II (Angst et al., 2003; Goldberg et al., 2001). The high frequency of BD-II found in clinical outpatient depression samples is mainly related to interview methods. These include focusing more on overactivity than on mood change; use of semi-structured interviews; interviews by clinicians; and interviews of family members or close friends (Benazzi, 2003b; Benazzi and Akiskal, 2003b). The diagnosis of BD-II has higher inter-rater reliability and more correct diagnoses of BD-II and other mood disorders by these methods (Benazzi and Akiskal, 2003a; Brugha et al., 2001; Dunner and Tay, 1993; Simpson et al., 2002).
By strictly following the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (SCID-CV), hypomanic symptoms cannot be assessed during an MDE (Dunner and Tay, 1993). Instead, our studies in Italy always require the assessment of hypomanic symptoms using the Hypomania Interview Guide. In mixed depression, hypomanic symptoms of high mood and increased self-esteem were absent. The core hypomanic symptoms of mixed depression were irritability, racing thoughts, psychomotor agitation and talkativeness (Akiskal and Benazzi, 2003). Systematic probing, and not spontaneous reporting, showed the presence of hypomanic symptoms during depression (which are less severe than manic symptoms and therefore less easily observable) (Benazzi and Akiskal, 2003a).
In our studies, hypomanic symptoms of mixed depression had to last at least one week and be present at the time of the interview. Patients were off psychoactive drugs for at least two weeks in order to avoid including antidepressant-induced mixed states (Akiskal and Pinto, 1999). Cross-sectional interviews were performed when individuals presented voluntarily for treatment of depression. Probing for BD-II followed soon after the diagnosis of depression was given, in order to avoid a possible bias related to the knowledge of bipolar signs (Ghaemi et al., 2002). The Table shows a picture of our current sample.
Mixed depression was more common in BD-II than in MDD. However, an interesting finding was that mixed depression was not uncommon in MDD. The best definition (i.e., the most clinically useful definition as a cross-sectional marker of BD-II) of mixed depression was found to be one based on a minimum of three hypomanic symptoms during major depression (Benazzi, 2001), compared to definitions based on combinations of specific hypomanic symptoms. This definition of mixed depression was similar to that used in mixed mania. Mixed depression had the best combination of sensitivity and specificity for BD-II diagnosis, as compared to several markers of BD-II, such as atypical depression, young age at onset, many MDE recurrences or family history (Benazzi, 2003c, 2002a, 2000; Ghaemi et al., 2002). An important finding was that a family history of BD in patients with MDD mixed depression was similar to that of patients with BD-II and that it was significantly higher than for MDD non-mixed depression. This finding was replicated by Sato et al. (2003).
Akiskal HS (2003), Validating 'hard' and 'soft' phenotypes within the bipolar spectrum: continuity or discontinuity? J Affect Disord 73(1-2):1-5.
Akiskal HS, Benazzi F (2003), Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 73(1-2):113-122.
Akiskal HS, Maser JD, Zeller PJ et al. (1995), Switching from 'unipolar' to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry 52(2):114-123.
Akiskal HS, Pinto O (1999), The evolving bipolar spectrum. Prototypes I, II, III, and IV. Psychiatr Clin North Am 22(3):517-534, vii.
Altshuler LL, Post RM, Leverich GS et al. (1995), Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 152(8):1130-1138 [see comment].
Angst J, Gamma A, Benazzi F et al. (2003), Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 73(1-2):133-146 [see comment].
Benazzi F (1997), Prevalence of bipolar II disorder in outpatient depression: a 203-casestudy in private practice. J Affect Disord 43(2):163-166.
Benazzi F (2000), Depressive mixed states: unipolar and bipolar II. Eur Arch Psychiatry Clin Neurosci 250(5):249-253.
Benazzi F (2001), Sensitivity and specificity of clinical markers for the diagnosis of bipolar II disorder. Compr Psychiatry 42(6):461-465.
Benazzi F (2002a), Which could be a clinically useful definition of depressive mixed state? Prog Neuropsychopharmacol Biol Psychiatry 26(6):1105-1111.
Benazzi F (2002b), Depressive mixed state frequency: age/gender effects. Psychiatry Clin Neurosci 56(5):537-543.
Benazzi F (2003a), Frequency of bipolar spectrum in 111 private practice depression outpatients. Eur Arch Psychiatry Clin Neurosci 253(4):203-208.
Benazzi F (2003b), Diagnosis of bipolar II disorder: a comparison of structured versus semistructured interviews. Prog Neuropsychopharmacol Biol Psychiatry 27(6):985-991.
Benazzi F (2003c), Bipolar II depressive mixed state: finding a useful definition. Compr Psychiatry 44(1):21-27.
Benazzi F (2003d), Bipolar II disorder and major depressive disorder: continuity or discontinuity? World J Biol Psychiatry 4(4):166-171.
Benazzi F (2003e), Depression with racing thoughts. Psychiatry Res 120(3):273-282.
Benazzi F, Akiskal HS (2001), Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes. J Affect Disord 6(1-3)7:115-122.
Benazzi F, Akiskal HS (2003a), Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J Affect Disord 73(1-2):33-38.
Benazzi F, Akiskal HS (2003b), The dual factor structure of self-rated MDQ hypomania: energized-activity versus irritable-thought racing. J Affect Disord 73(1-2):59-64.
Benazzi F, Akiskal HS (2003c), Clinical and factor analytic-validation of depressive mixed states: a report from the Ravenna-San Diego collaboration. Current Opinion in Psychiatry 16(suppl 2):S71-S78.
Brugha TS, Jenkins R, Taub N et al. (2001), A general population comparison of the Composite International Diagnostic Interview (CIDI) and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). Psychol Med 31(6):1001-1013.
Dunner DL, Tay LK (1993), Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression. Compr Psychiatry 34(5):303-307.
Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK (2003), Antidepressants in bipolar disorder: the case for caution. Bipolar Disord 5(6):421-433.
Ghaemi SN, Ko JY, Goodwin FK (2002), "Cade's disease" and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry 47(2):125-134 [see comment].
Goldberg JF, Harrow M, Whiteside JE (2001), Risk for bipolar illness in patients initially hospitalized for unipolar depression. Am J Psychiatry 158(8):1265-1270.
Judd LL, Akiskal HS, Schettler PJ et al. (2003), A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 60(3):261-269.
Kendell R, Jablensky A (2003), Distinguishing between the validity and utility of psychiatric diagnoses. Am J Psychiatry 160(1):4-12.
Koukopoulos A, Koukopoulos A (1999), Agitated depression as a mixed state and the problem of melancholia. Psychiatr Clin North Am 22(3):547-564.
Maj M, Pirozzi R, Magliano L, Bartoli L (2003), Agitated depression in bipolar I disorder: prevalence, phenomenology and outcome. Am J Psychiatry 160(12):2134-2140 [see comment].
McElroy SL, Keck PE Jr, Pope HG Jr et al. (1992), Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry 149(12):1633-1644 [see comments].
Perugi G, Akiskal HS, Micheli C et al. (1997), Clinical subtypes of bipolar mixed states: validating a broader European definition in 143 cases. J Affect Disord 43(3):169-180.
Perugi G, Akiskal HS, Micheli C et al. (2001), Clinical characterization of depressive mixed state in bipolar-I patients: Pisa-San Diego collaboration. J Affect Disord 67(1-3):105-114.
Sato T, Bottlender R, Schroter A, Moller HJ (2003), Frequency of manic symptoms during a depressive episode and unipolar 'depressive mixed state' as bipolar spectrum. Acta Psychiatr Scand 107(4):268-274.
Simpson SG, McMahon FJ, McInnis MG et al. (2002), Diagnostic reliability of bipolar II disorder. Arch Gen Psychiatry 59(8):736-740.